Immunology and Microbiology

Introduction

In the early 1960s, a small group of investigators focused on experimental models of human autoimmune diseases established the Scripps Clinic and Research Foundation as a preeminent center for immunopathological research. Their research program expanded rapidly and soon included basic investigations of both the innate and acquired immune systems and virus-immune interactions as a part of The Scripps Research Institute. These efforts resulted in many seminal contributions to basic immunology and virology including Nobel prize-winning studies on the innate immune system and election of several members of the department to the National Academy of Sciences. The strengths were further enhanced by the addition of groups working on infectious disease, first in La Jolla, CA, and then in Jupiter, FL, to form the current bicoastal Department of Immunology and Microbiology. The Department is home to several consortia investigating major problems at the intersection of virology and immunology, including vaccine science.

A current focus of several investigators in the Department is rational vaccine design, applied particularly to HIV, a program that involves extensive collaborations with researchers in other departments at TSRI and with investigators across the globe. TSRI includes several of the most cited scientists in HIV research. Their studies span many fields from computational protein design to structural biology to classical virology to the analysis of immune responses. A number of investigators are focused on emerging human pathogens, including particularly filoviruses, such as Ebola virus, arenaviruses, such as Lassa virus and flaviviruses, such as Zika virus, again using tools ranging from structural biology to mechanistic studies of cellular immunity to genomic studies. Hepatitis viruses, HBV and HCV, as well as lymphocytic choriomeningitis (LCMV) are similarly a keen focus of research. The Department houses several internationally recognized centers of discovery and development including the NIH-funded Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID), the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Consortium and the Viral Hemorrhagic Fever Immunotherapeutic Consortium (VIC).

Another focus of the Department is the biology of B cells, cells that produce antibodies. Investigators seek to understand the mechanisms of immune tolerance by which antibodies remove pathogens from the body but do not, in a healthy person, attack the body’s own cells. An important advance was the identification of receptor editing as the most significant mechanism of B-cell tolerance. The Department also intensively studies B-cell memory, the means by which first contact with a pathogen educates the body’s immune system so that response on second contact is much more effective. This memory is of course key in vaccine-mediated protection. Another key focus of investigation is how antibody diversity, necessary to protect us from many different pathogens, is generated. Department laboratories also intensively study and engineer antibodies as potential therapeutic agents in their own right, targeting pathogens and tumors. The study of the innate immune system, composed of diverse immunocyte subsets, sensors for microbial components and inflammatory mediators, especially interferons, has led to the identification of novel defense mechanism in viral infections. Moreover, aberrant recognition of self-molecules by the innate system appears to be central to the pathogenesis of several autoimmune syndromes, such as lupus, multiple sclerosis and type I diabetes. These fundamental findings constitute the basis for current efforts in collaboration with outstanding colleagues in the Chemistry Department at TSRI to develop novel treatments for a wide spectrum of inflammatory disorders.

The Department has traditionally maintained a sharp focus on the development and function of T cells, cells that orchestrate B cell-mediated immunity and also directly engage and kill virally infected or malignant cells. The critical role of these cells is highlighted in a number of disease states. For example, AIDS is a consequence of the profound loss of CD4-positive T cells, and cytotoxic T cells are crucial in controlling persistent infections such as LCMV and HIV. Increased susceptibility to infections and tumors with age correlates with a decline in T-cell function. Dysregulation of T cells significantly contributes to chronic inflammation and autoimmunity. TSRI investigators have made seminal contributions to understanding how nascent T cells develop from stem cell precursors in the bone marrow, how they are maintained throughout life and how they become activated into functional effector and memory T cell subsets during infections and vaccinations. TSRI investigators have developed multiple small molecules and engineered antibodies to modulate T-cell activities, including those now in clinical trials for multiple sclerosis, inflammatory bowel disease and blood cancers. Our investigators are also leveraging novel high-throughput small molecule and genetic screening approaches developed at TSRI to identify new therapies and therapeutic targets, to improve adoptive immunotherapy for cancer and to control or cure persistent infections and autoimmune diseases.

In short, the Department combines a deep mechanistic understanding of immune responses and of pathogens with resources for, and a strong commitment to, translating this knowledge into treatments and cures for infectious disease, cancer and autoimmunity.